Ent-pimara-8(14), 15-dien-19-oic acid isolated from the roots of Aralia cordata inhibits induction of inflammatory mediators by blocking NF-kappaB activation and mitogen-activated protein kinase pathways.
Macrophages play central roles in the innate immune system. The roots of Aralia cordata are widely used in Oriental medicine as a remedy for arthritis. During our program to screen medicinal plants for potential anti-inflammatory compounds, ent-pimara-8(14), 15-dien-19-oic acid (pimaradienoic acid; PA) was isolated from the roots of A. cordata. We examined the effect of PA on pro-inflammatory mediators in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. PA was found to significantly inhibit the production of nitric oxide (NO), prostaglandin E(2) (PGE(2)), and interleukin-6 (IL-6), as well as the expressions of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), and IL-6. Furthermore, we examined whether mitogen-activated protein kinases (MAPKs) and phosphatidylinositol 3-kinase (PI3K) signaling pathways are involved in LPS-induced RAW 264.7 cells. We found that a p38 inhibitor (SB203580) and an ERK 1/2 inhibitor (PD98059) significantly affected LPS-induced IL-6 production. In contrast, a JNK 1/2 inhibitor (SP600125) and PI3K inhibitor (wortmannin or LY294002) did not block the induction of IL-6 production by LPS. The LPS-induced phosphorylation of p38 MAPK and extracellular signal-regulated kinase 1/2 (ERK1/2) was inhibited by PA, but not the phosphorylation of JNK 1/2 and AKT (Ser473). Moreover, PA suppressed I kappaB alpha degradation, NF-kappaB activation and luciferase activity. These results suggest that PA isolated from A. cordata has a potential regulatory effect on inflammatory iNOS, COX-2 and IL-6 expression through blockade of the phosphorylation of MAPKs following I kappaB alpha degradation and NF-kappaB activation.
Kang
Ok-Hwa
OH
College of Pharmacy and Wonkwang-Oriental Medicines Research Institute, Wonkwang University, Iksan, Jeonbuk, 570-749, Republic of Korea.
Chae
Hee-Sung
HS
Choi
Jang-Gi
JG
Oh
Yoo-Chang
YC
Lee
Young-Seob
YS
Kim
Jong-Hak
JH
Seung
Man-Jun
MJ
Jang
Hye-Jin
HJ
Bae
Ki-Hwan
KH
Lee
John-Hwa
JH
Shin
Dong-Won
DW
Kwon
Dong Yeul
DY
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000302:isolation & purification / Q000494:pharmacology*; D027983:Aralia / Q000737:chemistry; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000378:metabolism; D004224:Diterpenes / Q000302:isolation & purification / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D020672:I-kappa B Proteins / Q000187:drug effects / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008518:Medicine, East Asian Traditional; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000187:drug effects* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D004224:Diterpenes; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D015850:Interleukin-6; D016328:NF-kappa B; C008911:pimaric acid; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D020928:Mitogen-Activated Protein Kinases